Acute uncomplicated urinary tract infections (UTIs) occur in an estimated 7-11 million women each year and annual costs of caring for these women are thought to approach $1.6 billion. While most young women experience only sporadic episodes of cystitis, approximately 20-30% suffer from recurrent infections, 5% from highly recurrent infections, and as many as 5-10% develop acute pyelonephritis, often necessitating hospitalization and parenteral antimicrobials. In the aggregate, UTIs in young women result in substantial morbidity, time lost from work, and medical costs. An improved understanding of the pathogenic mechanisms underlying recurrent UTIs and pyelonephritis could result in novel approaches to their prevention and reduced morbidity and antimicrobial use. Behavioral factors such as sexual and contraceptive practices have been shown to be strongly associated with risk of recurrent UTI (RUTI) in these women, and there is increasing evidence that recurrent RUTIs are also associated with genetic factors. Genetic variation has been used to implicate genes in the susceptibility to many infections. The main objective of this project is to determine whether DNA variations in selected candidate host genes influence human susceptibility to RUTI or pyelonephritis. Based on accumulating evidence implicating them as important in animal models of UTI, the candidate genes selected for study are toll-like receptors (TLR2, TLR4, and TLR5), chemokine receptors (CXCR1 and CXCR2) and interferon gamma receptors (IFN-gammaR1 and IFNgammaR2). In this project, we will perform full gene sequencing of these candidate genes in 100 women with a strong family history of RUTI or pyelonephritis to discover novel nucleotide variations in these groups. We will then examine, via a case-control study of 1700 women that identifies all incident cases and two population-based control groups, whether known or novel genetic variations in these candidate genes are associated with the syndromes of RUTI and/or pyelonephritis. We will also determine how genetic variations may modify the association between behavioral risk factors and RUTI and pyelonephritis. A better understanding of the role of genetics in the pathogenesis of RUTI and pyelonephritis, and the relationship between behavioral factors and genetic variations, is critical to the development of optimal prevention and management strategies for these very common syndromes in women.